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Translational Control of Megakaryocyte and Platelet Function in Sepsis

脓毒症中巨核细胞和血小板功能的转化控制

基本信息

批准号：
9577464
负责人：
Matthew Thomas Rondina
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9577464
关键词：
Abnormal Platelet Acute Adverse effects Affect Agonist Applications Grants Attention Biological Models Blood Platelets Cell physiology Cells Data Disease Eukaryotic Initiation Factor-4E Event FRAP1 gene Gene Expression Gene Expression Regulation Genes Genetic Genetic Translation Goals Health Human Impairment In Vitro Inflammation Inflammatory Interferons MAP Kinase Gene Megakaryocytes Messenger RNA Mitogen-Activated Protein Kinases Modeling Mus Outcome Pathogenesis Pathway interactions Phenotype Phosphotransferases Platelet Count measurement Production Protein Biosynthesis Protein-Serine-Threonine Kinases Proteins Regulation Ribosomes Sepsis Signal Pathway Signal Transduction Techniques Testing Thrombopoiesis Translating Translation Initiation Translational Activation Translational Regulation Translations adverse outcome clinical effect cytokine human model in vivo in vivo Model inflammatory milieu inhibitor/antagonist kinase inhibitor mouse model novel protein expression response ribosome profiling septic septic patients transcriptome virtual

项目摘要

Summary/Abstract Regulation of gene expression at the translational level (i.e., mRNA-protein) is poorly understood in normal megakaryocytes, and it is virtually unknown if inflammatory diseases alter translational responses in megakaryocytes and platelets. With that said, inflammation contributes to the pathogenesis of numerous diseases such as sepsis, and inflammatory agonists are considered potent triggers of mRNA translation. This grant proposal will utilize human and mouse model systems (in vitro and in vivo) and state-of-the-art sequencing (ribosomal footprinting and eIF4E-enrichment) to determine how translational control pathways regulate megakaryocyte and platelet gene expression – in the setting of health and septic situations. Preliminary data supporting this project demonstrates that the mammalian target of rapamycin (mTOR) and the MAP kinase-interacting serine/threonine-protein kinase 1 (MNK1), two translational control pathways that converge on the initiation step of translation, regulate protein synthetic events and functions in megakaryocytes and platelets. These preliminary results have led to the hypothesis that the septic milieu will significantly modify mTOR and/or MNK1-dependent translation in megakaryocytes and platelets, resulting in inappropriate formation and function of platelets during the course of sepsis. Specific Aim1 will test the hypothesis that inflammatory agonists generated during sepsis will alter protein synthetic events in megakaryocytes and the formation of platelets in an mTOR and MNK1-dependent manner. Specific Aim 2 will determine how genetic deletion of mTOR or MNK1 regulates the ex vivo and in vivo function of platelets in the presence or absence of inflammation. Specific Aim 3 will test the hypothesis that the septic milieu activates the mTOR and/or MNK1 signaling pathways and thereby increases protein synthesis by platelets. It will also determine if deletion of mTor and/or Mnk1 in mouse platelets leads to adverse outcomes in murine models of sepsis. Successful completion of these aims will 1) identify translated mRNAs in megakaryocytes that are under mTOR and/or MNK1-dependent control and whether these translational signaling pathways regulate the final steps of platelet production, 2) delineate the effects of mTOR and MNK1 on functions of megakaryocytes and platelets in health and inflammation, 3) characterize inadvertent side- effects of clinically-used mTOR and MNK1 inhibitors on megakaryocytes and platelets, and 4) determine if mTOR or MNK1 in megakaryocytes and platelets regulate outcomes in models of sepsis. Data generated will immediately increase our understanding of how translational control pathways alter megakaryocyte and platelet functions in the setting of sepsis.

摘要/文摘